The modern laboratory mouse was derived from a diverse gene pool of multiple species of the Mus musculus genospecies complex from throughout Europe and Asia. The progenitors of laboratory mice were thus hybrid species, but they subsequently underwent a genetic bottleneck at the beginning of the last century. Thus, the genomes of inbred strains of mice, although homozygous, contain variable allelic contributions from this diverse origin, including endogenous retrovirus and retrovirus-like elements. Domestication of the mouse through international trading has also introduced over 60 infectious pathogens that can cause overt disease, as well as more subtle effects upon research. Burgeoning mouse populations and exchange among scientists have led to the re-emergence of many of these agents. Genetic alteration of the mouse often leads to atypical outcomes of these infections which confound research. Diet, bedding, water, behavior, and other factors also contribute to variable research results. Effective cancer research should take advantage of the opportunity to utilize the mouse as a genetically, microbially, and environmentally standardized animal model system, but this requires global awareness of the biology of the laboratory mouse.